High Risk Of Heparin-induced Thrombocytopenia Research Articles

AORTIC THROMBOSIS AFTER CARDIAC SURGERY FROM HEPARIN-INDUCED THROMBOCYTOPENIA

SESSION TITLE: Fellows Critical Care Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is a complication caused by exposure to heparin. Although incidence after cardiac surgery is of 0.3%, there is a 50% increase in mortality when HIT occurs [1]. CASE PRESENTATION: A 65-year-old male with history of diabetes mellitus presented with chest pain. Two days prior to coronary artery bypass grafting (CABG), coronary angiography revealed triple vessel disease. He received 3000 units of heparin for the procedure. He underwent on-pump CABG, where 19,500 units of heparin were given. After surgery, platelet count decreased with nadir of 105×103 /μL (40% decrease) on postoperative day (POD) 4. He complained of abdominal and lower extremities’ pain on POD 5. Computed tomography (CT) showed a thrombosed infrarenal aorta (Fig 1). Vascular team performed axillary and femoral artery bypass surgery. He complained of abdominal pain and CT showed dilated loops of bowel with pneumatosis intestinalis on POD 7. Laparotomy was performed and necrosed small bowel was resected. HIT was suspected due to thromboembolic events (4Ts score was 6; high risk of HIT) [2]. Particle Immuno-Filtration Assay (PIFA®) and Serotonin Release Assay (SRA) were ordered and results came negative. Assays were done for second time on POD 10 and PIFA® resulted negative. Echocardiogram revealed small thrombus in left ventricle apex on POD 11. Although SRA result was pending, heparin was discontinued and argatroban was administered. SRA test came positive on POD 12. Platelet count began recovering and there was no more thromboembolic event. Platelet count returned to normal at 5-month follow-up (Fig 2). DISCUSSION: There are two requirements to determine presence of HIT: a) clinical diagnosis and b) detection of heparin antibodies activating platelet (through positive SRA). Clinical diagnosis can be completed by use of 4Ts score [2] (Fig 3). If 4Ts score is more than 4 (intermediate risk), the serological tests should be performed. There are two types of tests for HIT: one is the antigen assay PIFA® and the other is the functional assay SRA. Both have high sensitivity of 90%. PIFA® is used for screening, has a specificity ranging from 50% to 89% and its result can be available within 15 minutes. SRA has a higher specificity of more than 90%. To confirm the diagnosis, SRA result should be positive, although several days may take to obtain result. CONCLUSIONS: If the serological test shows negative and HIT is still suspected clinically, the test should be repeated. High clinical suspicion should lead to termination of heparin and initiation of argatroban. Reference #1: Seigerman M., Cavallaro P., Itagaki S., Chung I., Chikwe J. Incidence and outcomes of heparin-induced thrombocytopenia in patients undergoing cardiac surgery in North America: an analysis of the nationwide inpatient sample. J Cardiothorac Vasc Anesth. 2014;28:98-102. Reference #2: East M.J., Cserti-Gazdewich M.C., Granton T.J. Heparin-induced thrombocytopenia in the critically ill patient. Chest. 2018; 154:678-690. Reference #3: Ortel T.L. Heparin-induced thrombocytopenia: when a low platelet count is a mandate for anticoagulation. Hematology Am Soc Hematol Educ Program. 2009;225-232. Fig 1; Contrast computed tomography (CT) showed total occlusion of the infrarenal abdominal artery and bilateral iliac arteries. DISCLOSURES: No relevant relationships by Youdelman Benjamin, source=Admin input No relevant relationships by Shinichiro Ikeda, source=Web Response No relevant relationships by Ronald Kaleya, source=Web Response No relevant relationships by Robert Rhee, source=Web Response

Treatment and Outcomes in Heparin-Induced Thrombocytopenia (HIT) in Patients with Neoplasm: A Single Centre Experience

Background: Heparin-induced thrombocytopenia (HIT) is an immune mediated, pro-thrombotic disorder associated with exposure to heparin and a substantial number of patients develop thrombosis (HITT) in the venous, arterial, or microvascular system. Treatment includes cessation of heparin and starting a non-heparin anticoagulant. Patients with cancer are already at high risk of venous thromboembolism (VTE) as well as recurrent VTE despite anticoagulant therapy and are also at higher risk of bleeding compared with patients without cancer. Consequently, cancer patients may not share similar outcomes as patients without cancer in the setting of HIT. We conducted a single-centre, retrospective study to evaluate baseline characteristics, treatments and outcomes in HIT patients with and without cancer. Methods: Medical records of all patients seen at our tertiary centre between November 1, 2006 and December 31, 2016 who tested positive for HIT antibodies and had a 4T score of 4 or higher were reviewed. Patients with cancer were defined as those who had any evidence of cancer, including myeloproliferative neoplasm (MPN), and/or receiving cancer treatment within 6 months prior to HIT diagnosis. Details of treatments and outcomes were captured up to 6 months after start of HIT treatment. Comparative statistics was performed between the cancer and non-cancer cohorts. Results: We identified 95 patients with confirmed HIT, of whom 39 (41%) had cancer and 41 (43%) had HITT as the index event. The mean age was 65 years (standard deviation 16) and 59% were female. Thirty (77%) cancer patients had at least 3 months of available records and 26 (67%) had at least 6 months, while 37 (66%) non-cancer patients had at least 3 months of available records and 27 (48%) had at least 6 months. Baseline demographics including cancer types are summarized in Table 1. The most common malignancy was polycythemia vera (PV), with those with MPN (7 PV, 2 essential thrombocythemia) representing 23% of the patients with cancer. Cancer patients were more likely to have a history of thromboembolic events prior to index heparin exposure and HIT diagnosis (79.5% vs. 53.6%, p=0.02) than those without cancer. Among patients with HITT, the two groups had similar incidences of pulmonary embolism and/or deep vein thrombosis, although a higher proportion of the non-cancer group had clots in other non-classic locations (32.1% vs. 10.3%, p=0.01) such as splanchnic thrombosis. A variety of non-heparin agents were used, including direct oral anticoagulants (Table 2), with most patients receiving either fondaparinux or argatroban followed by warfarin. The cancer group received fondaparinux more often than the non-cancer group (87.2% vs. 64.3%, p=0.02). In those alive with at least 6 months of follow-up, the median duration of non-heparin anticoagulation was 180 days for both cancer patients and non-cancer patients. During follow-up, 16 (17%) patients had a thrombotic event, 15 (16%) had major bleeding and 11 (12%) died among the 95 patients with HIT. The rates of subsequent thrombosis, bleeding events, and death were similar between the two cohorts over the 6-month follow-up period (Table 3). None of the deaths were from thrombotic or bleeding events but the cause of death for one patient with cancer was unknown. Conclusion: Patient outcomes following a diagnosis of HIT appear similar between patients with and without cancer, with high rates of subsequent thrombosis and major bleeding. Patients with MPN might have a higher risk of HIT. Further studies are warranted to confirm these findings and determine if direct oral anticoagulants might be efficacious and safe in patients with HIT. Disclosures Lee: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; LEO Pharma: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. OffLabel Disclosure: Direct oral anticoagulants and fondaparinux were used as non-heparin anticoagulants for the treatment of heparin induced thrombocytopenia.

Frequency and Clinical Impact of Platelet Factor 4-Specific Antibodies in Patients Undergoing Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) provides circulatory support in patients with severe heart failure, but the frequent use of unfractionated heparin exposes patients to high risk of heparin-induced thrombocytopenia (HIT). We prospectively evaluated the development and clinical impact of platelet factor 4 (PF4)-specific antibodies (Abs) during ECMO and whether specific biological characteristics could predict HIT. From 2014 to 2018, we studied 57 adults who underwent an ECMO for at least 5 days. The plasma samples collected daily were tested for PF4-specific Abs using immunoassays to detect immunoglobulin (Ig) G, A, and M isotypes or only IgG. Serotonin release assay was performed without and with PF4 to detect pathogenic Abs. Twenty-nine patients (50%) were positive for PF4-specific Abs (IgG, A, M), with IgG in 17/57 (30%) and 16 of them (94%) were immunized within 10 days. PF4-specific IgG Abs did not affect the clinical or biological course of most patients. HIT was suspected in only two patients with ECMO circuit dysfunction and unexpected platelet count decrease after day 5. High levels of PF4-specific IgG were detected in both patients, and HIT was confirmed by a serotonin release assay, which was also more sensitive when exogenous PF4 was present. PF4-specific Abs are common during ECMO but are mostly non-pathogenic and not associated with a less favorable prognosis. However, an abnormal platelet count evolution, in particular if associated with ECMO circuit dysfunction, should prompt the search for pathogenic PF4-specific IgG.

Heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a clinical immune-mediated syndrome; symptoms of HIT result from the development of arterial and venous thrombosis and are correlated with the severity of the thrombocytopenia. In all patients receiving heparin preparations in intensive care units, platelet counts should be monitored every 2-3 days throughout therapy, particularly during days 4-14 when HIT is most likely to develop. The major screening tests should always involve a clinical assessment of HIT probability (4Ts or HEP scoring systems) and enzymatic immunoassays (IgG antibodies) for patients with a moderate to high risk of HIT. The full possibilities of such advanced diagnostic procedures are limited in Poland because functional tests are still not widely available. If the diagnosis is questionable, all heparin preparations should be withdrawn and an alternative method of anticoagulation instituted until HIT has been conclusively excluded. The use of new-generation anticoagulants (direct thrombin or Xa factor inhibitors) is currently considered the treatment of choice. Old-generation anticoagulants should not be administered (vitamin K antagonists) as they can aggravate thrombosis. If administered, their action should be reversed by vitamin K once HIT is confirmed. Antithrombotic therapy with "new" anticoagulants should be carried out at least until platelet counts return to the baseline values; the recommended duration of therapy is 4 weeks in patients with isolated thrombocytopenia or 4 months in those with thrombotic complications. Vitamin K antagonists should not be applied until the normal platelet count is restored (usually > 150 G L⁻¹). When the therapy with vitamin K antagonists is reintroduced, "old" antagonists should be administered simultaneously with a "new" anticoagulant for at least 5 days due to an initial decrease in protein C concentration concentration, provided that the therapeutic value of INR is maintained (> 2) for at least 2 days.

Polymorphism of the Fcγ Receptor II as a Possible Predisposing Factor for Heparin-Induced Thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) represents a serious complication of heparin treatment. IgG antibodies binding platelet factor 4 (PF4) and heparin trigger the clinical manifestations of HIT. However, only a portion of the antibodies have the ability to activate platelets, and these can be identified by a platelet aggregation test (functional testing). However, this expression has been detected to have a molecular cause, which is a mutation of FcγRIIa. The FcγRIIa receptor is responsible for the activation of platelets by antibodies in HIT. To determine HIT, impedance aggregometry using the Multiplate analyzer (MEA) as heparin-induced aggregation technique and the Technozym HIT IgG ELISA test were used. The MEA method uses sensitization of donor platelets with patient plasma in the presence of heparin at a concentration of 0.5 IU/mL. The results were compared with the ELISA test. Mutation of FcγRHa was assessed using the asymmetric real-time PCR method that is based on the reaction with two hybridization probes and melting curve analysis. Examined were 100 patients at a clinically intermediate and higher risk of HIT according to the 4T's score. All samples were examined by the ELISA test and MEA, with positive samples being further confirmed by high-concentration heparin. In the group of patients, 10.0% were positive by MEA as compared with 4% determined by ELISA. The results of genetic analysis of FcγRIIa did not provide statistically significant differences between positive patients found by the functional test as well as the ELISA test and seronegative patients. The genetic mutation FcγRIIa is a predisposing factor for manifestation of HIT in the form of thrombocytopenia, but the process of seroconversion apparently needs another inducing factor. Therefore, the examination of mutations can be classified as predisposing factors rather than to confirm the diagnosis of HIT.

The Advantages and Limitations of Impedance Aggregometry in Detection of Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) represents a serious complication of heparin treatment. IgG antibodies binding platelet factor 4 (PF4) and heparin trigger the clinical manifestations of HIT. However, only a portion of the antibodies have the ability to activate platelets, and these can be identified by a platelet aggregation test (functional testing). Current methods HIPA and SRA are time-consuming and difficult if HIT is clinically suspected; therefore, numerous new methods have recently been developed. To determine HIT, impedance aggregometry using the Multiplate analyzer (MEA) as heparin-induced aggregation techniques and the Technozym HIT Ig ELISA test were used. The MEA method uses sensitization of donor platelets with patient plasma in the presence of heparin at a concentration of 0.5 IU/mL. The results were compared with the ELISA test. We examined 190 patients at clinically intermediate and higher risk of HIT according to the 4T score. All samples were examined by the ELISA test and MEA, with positive samples being further confirmed by high-concentration heparin. The methodology was modified with respect to the dilution for high positive samples and assessment has been extended to an index of inhibition. In the studied group, we demonstrated that MEA has sufficient sensitivity and higher specificity. In the group of patients, 10.0% showed positive results by MEA as compared with 7.3% determined by ELISA. Unlike the ELISA methods of the same quality, MEA is more suitable for detecting platelet-activating HIT antibodies in practice.

Optimal dose of bivalirudin in dialysis patients at high risk of heparin-induced thrombocytopenia undergoing percutaneous coronary intervention: case report

Bivalirudin is a direct thrombin inhibitor that has been approved for use in patients with or at risk for heparin-induced thrombocytopenia undergoing percutaneous coronary intervention. The efficacy of bivalirudin has been well documented in the setting of percutaneous coronary intervention, but there are only few data on its use in chronic dialysis-dependent patients. Bivalirudin is mainly eliminated enzymatically (80%) and to a lesser extent renally (20%). Nevertheless, in patients with chronic kidney disease a substantial increase in coagulation time and bleeding complications has been reported. Therefore, dosage adjustments may be necessary in patients with renal impairment. Dosing and monitoring recommendations in dialysis patients have not yet been established. We describe the case of a 77-year-old man with non-ST-elevation acute coronary syndrome complicated by heparin-induced thrombocytopenia and acute renal failure requiring dialysis treatment. During percutaneous coronary intervention, anticoagulant therapy with bivalirudin was administered at non-standard doses, though already documented in the literature.

Bivalirudin Versus Heparin as an Anticoagulant During Extracorporeal Membrane Oxygenation: A Case-Control Study

Heparin-based anticoagulation for patients undergoing extracorporeal membrane oxygenation has many limitations, including a high risk of heparin-induced thrombocytopenia. However, little experience with other anticoagulants in these patients has been described. The aim of this study was to compare bivalirudin-based anticoagulation with heparin-based protocols in a population of patients treated with venovenous or venoarterial extracorporeal membrane oxygenation. In this case-control study, 10 patients received bivalirudin (cases) and 10 heparin (controls). The target activated partial thromboplastin time (aPTT) was 45 to 60 seconds. None. aPTT variations >20% of the previous value were much more frequent in patients treated with heparin than in patients receiving bivalirudin (52 v 24, p < 0.001). The number of corrections of the anticoagulant dose was higher in the heparin group compared with the bivalirudin group (58 v 51), although it did not reach statistical significance. Bleeding, thromboembolic complications, extracorporeal membrane oxygenation (ECMO) support duration, mortality, and the number of episodes of aPTT >80 seconds were not different between the 2 groups. A further analysis was performed in the bivalirudin group according to the presence of acute renal failure requiring continuous venovenous hemofiltration. The median bivalirudin dose in patients with or without hemofiltration was 0.041 (0.028-0.05) mg/kg/h and 0.028 (0-0.041) mg/kg/h, respectively (p = 0.2). Bivalirudin-based anticoagulation may represent a new method of anticoagulation for reducing thromboembolic and bleeding complications, which still jeopardize the application of extracorporeal membrane oxygenation. Moreover, bivalirudin is free from the risk of heparin-induced thrombocytopenia. Higher doses of bivalirudin may be needed in patients undergoing hemofiltration.

Binding of heparin‐dependent antibodies to PF4 modified by enoxaparin oligosaccharides: evaluation by surface plasmon resonance and serotonin release assay

The minimal structural requirements of low-molecular-weight heparins that determine the risk of developing heparin-induced thrombocytopenia (HIT) are not fully defined. The ability of enoxaparin-derived oligosaccharides (OS) to induce platelet activation and exposure of platelet-factor 4 (PF4) epitopes recognized by antibodies developed in HIT was studied by surface plasmon resonance (SPR) and serotonin release assay. Decasaccharides with ≥ 11 sulfate groups induced platelet activation in the presence of plasma from patients with confirmed HIT. Serotonin release of > 80% without full inhibition at 100 μg mL(-1) was achieved with decasaccharides containing 14 or 15 sulfate groups, 2 dodecasaccharides and 2 tetradecasaccharides. An SPR method was developed using purified PF4 immobilized on carboxymethylated dextran. Antibodies from all HIT samples bound to PF4/heparin in SPR assays with resonance units (RU) ratio of 109-173 with HIT plasma vs. 88-93 with control plasma. RU ratios > 100 were measured when PF4 was pre-incubated with OS with ≥ 10 saccharide units and one octasaccharide containing 10 sulfate groups. RU ratios > 140, similar to those measured when PF4 was pre-incubated with unfractionated heparin or enoxaparin, were obtained with purified dodeca- and tetradecasaccharides. RU values strongly correlated with the number of sulfate groups in the decasaccharides tested (r = 0.93, P = 0.02). LMWHs with fragments > 10 saccharides and a large number of sulfate groups are more likely to be associated with a higher risk of HIT. These structure-activity relationships were independent of the ability of the OS to bind antithrombin.

Topical Issues in Venous Thromboembolism

Despite clear guidelines and the availability of effective treatments, venous thromboembolism (VTE) remains relatively common, particularly in the hospital setting. This paper reviews topical issues in VTE, in terms of treatments, data and guidelines. Existing anticoagulants have several limitations. Bleeding risk is a concern with all anticoagulants. Vitamin K antagonists are the mainstay of oral anticoagulant therapy, but they are limited by the need for frequent monitoring. Unfractionated heparin (UFH) is limited by an inconvenient route of administration (continuous intravenous infusion) and a higher risk of heparin-induced thrombocytopenia and bleeding compared with low molecular weight heparins (LMWH). LMWH have a more predictable pharmacokinetic profile and greater bioavailability than UFH, which permits weight-adjusted LMWH dosing without the need for monitoring in most patients. LMWH also have a more convenient dosing strategy than UFH (once-daily subcutaneous injection). Fondaparinux is a selective inhibitor of factor Xa and, like LMWH, does not require monitoring. The efficacy of fondaparinux in long-term VTE treatment remains to be established. The optimal time to initiate thromboprophylaxis in patients undergoing orthopaedic surgery remains controversial. Initiating thromboprophylaxis just before or soon after surgery (the 'just-in-time' strategy) achieves better thromboprophylaxis but could increase the risk of bleeding complications. Balancing the need for extended thromboprophylaxis after major surgery with the need to minimize bleeding remains an important consideration. Despite clear guidelines, thromboprophylaxis is widely underused, particularly in medical patients, in whom rates as low as 28% have been reported. Electronic alert systems may be of value for increasing the use of adequate thromboprophylaxis. The use of different definitions of VTE and bleeding in clinical trials, together with missing venography data, conflicting guidelines in patients undergoing total hip or knee arthroplasty, and the limited amount of data in children, also make VTE prevention and management more difficult. Administering thromboprophylaxis to a wider group of patients, employing the 'just-in-time' protocols, ensuring adequate duration of thromboprophylaxis, combining different methods of thromboprophylaxis and developing new anticoagulants should help to improve thromboprophylaxis.

Therapie der venösen Thromboembolie

The main objectives in the treatment of venous thromboembolism are to prevent clot extension and pulmonary embolism, to reduce mortality and to prevent recurrent thromboembolic events as well as postthrombotic disorders. Initial and effective anticoagulation with heparin, preferably with low molecular weight heparin (LMWH), or with fondaparinux is the most important measure. Unfractioned heparin (UFH) is as effective as LMWH, but requires coagulation-monitoring and is associated with a higher risk of heparin-induced thrombocytopenia. In patients with renal insufficiency direct determination of anti-factor Xa activity and dose adjustment is recommended, since drug accumulation can occur over time. In those patients UFH instead of LMWH might be favored. Long-term treatment should be administered with vitamin K-antagonists (INR-target range 2-3) for a duration of 3 to 6 months. In case of recurrent venous thromboembolism, indefinite therapy is recommended. Additional treatment with compression stockings is reasonable. Patients who do not require hospital treatment for other conditions, who have a low bleeding risk, no excessive venous congestion and no symptomatic pulmonary embolism can safely be treated at home. In most cases bed rest is not necessary. Thrombolysis or surgical thrombectomy is seldomly indicated in severe thromboembolism.

Risk of heparin-induced thrombocytopenia in patients receiving thromboprophylaxis

Heparin-induced thrombocytopenia (HIT) is a clinicopathological syndrome associated with heparin therapy that is characterized by a decrease in platelet counts and/or the development of a new thrombosis. Two types of HIT exist, type I is nonimmune and self-resolves, whereas type II is immune-mediated and clinically important. The formation of antibodies against the platelet factor 4–heparin complexes results in platelet activation and thrombin formation, which lead to an increased risk of thrombosis. Unfractionated heparin is associated with a higher risk of HIT than low-molecular-weight heparins. Surgical patients, particularly those undergoing orthopedic or cardiac surgery, are at higher risk of HIT than medical patients. Treatment of HIT involves heparin cessation together with anticoagulation with direct thrombin inhibitors or indirect factor Xa inhibitors.

Antibodies to platelet factor 4-heparin after cardiopulmonary bypass in patients anticoagulated with unfractionated heparin or a low-molecular-weight heparin : clinical implications for heparin-induced thrombocytopenia.

Cardiopulmonary bypass (CPB) induces platelet activation with release of platelet factor 4 (PF4), and patients are exposed to high doses of heparin (H). We investigated whether this contributes to the development of antibodies to H-PF4 and heparin-induced thrombocytopenia (HIT). CPB was performed with unfractionated heparin (UFH) in 328 patients. After surgery, patients received UFH (calcium heparin, 200 IU. kg-1. d-1) (group 1, n=157) or low-molecular-weight heparin (LMWH, Dalteparin, 5000 IU once daily) (group 2, n=171). Eight days after surgery, antibodies to H-PF4 were present in 83 patients (25.3%), 46 in group 1 and 37 in group 2 (P=0.12). Most patients (61%) had IgG1 to H-PF4, but only 8 samples with antibodies induced platelet activation with positive results on serotonin release assay. HIT occurred in 6 patients in group 1, but no thrombocytopenia was observed in subjects receiving LMWH, although 2 had high levels of antibodies with positive serotonin release assay results. When antibodies to H-PF4 were present, mean platelet counts were lower only in patients with FcgammaRIIA R/R131 platelets. These results provide evidence that the development of antibodies to H-PF4 after CPB performed with UFH is not influenced by the postoperative heparin treatment. The antibodies associated with high risk of HIT are mainly IgG1, which is present at high titers in the plasma of patients continuously treated with UFH.